Impotence in males is normally defined as the inability to copulate including inability to achieve penile erection or ejaculation or both. More particularly, impotence in males is the inability to achieve and/or maintain penile erection sufficient for intercourse. Male impotence is quite prevalent in India and the world over, the incidence being higher in higher age groups. It is estimated that about 7% of the male population in the age group of 18 to 50 years are impotent, the incidence being much higher in the males in the age group of from 55 to 80 years. In the USA, alone it has been estimated that over 10 million males suffer from impotence due to erectile dysfunction, which in majority of them is because of organic rather than psychogenic reasons. In India the figures are considerably higher, given the population and the number of cases that go unreported. In the remaining, psychogenic etiology is believed to be the cause of dysfunction.
Female sexual arousal dysfunction (FSAD) is the inability of the female to be sexually aroused, clitoral erectile dysfunction, inability to copulate and failure to achieve orgasm.
The most common organic diseases responsible for male impotence and sexual dysfunction in females are hypertension, coronary artery disease and diabetes. Another major factor responsible for male impotence is the contractility of the smooth muscle within the corpus cavernosum penis and penile arteries that impede the modulation of penile blood flow by physiological regulators. In the females, the sexual dysfunction is attributable to lack of blood flow in the vaginal area, particularly, the clitoral tissues, which causes clitoral erectile dysfunction, decreased sexual stimulation, dryness and lack of lubrication and pain during intercourse. A similar mechanism, i.e., increased contractility of smooth vascular muscle impedes the modulation of flow of blood in coronary arteries of patients suffering from hypertension or diabetes.
Several other causes for male impotency and female sexual arousal dysfunction have also been studied and reported. Most common amongst them include disorders of endocrine glands such as testicular failure and hyperprolactenemia in males, adverse effects of several drugs such as antidepressants, antihypertensives, anticholinergics, antipsychotics, drug abuse and drug addiction, nicotine abuse, penile and vaginal diseases, neurological diseases, anterior temporal lobe lesions, diseases of the spinal cord and vascular diseases.
Male penile erectile dysfunction has been the subject of greater study than female sexual arousal dysfunction. Vascular diseases such as essential hypertension, aortic occlusion, atherosclerotic occlusion, venous leak and diseases of sinusoid spaces often result in male impotence.
Disorders such as essential hypertension, coronary artery disease and diabetes involve an increase in smooth muscle tone, which limit modulation of blood flow in the vital organs and vascular bed. In U.S. Pat. No. 5,658,936, granted to Kifor and Williams, it is suggested that an imbalance between locally produced Angiotensin II and nitric oxide (NO) leads to an inappropriate tone of vascular smooth muscle resulting in increased blood pressure and altered regional blood flow.
Both vascular and ccp smooth muscles are contracted by angiotensin II. However, this peptide is not believed to be an important regulator of penile blood blow. In fact, it is widely believed that antihypertensive agents, such as ACE inhibitors and angiotensin II antagonists cause sexual dysfunction in males.
While several studies have been conducted to link antihypertensive agents with erectile dysfunction, the results have not been conclusive, but rather, inconsistent. Some drugs which are reported to cause impotence in one case have been reported to be useful in the treatment of impotence in another case.
Some studies have, determined that ACE inhibitors did cause impotence. [Wallcy. T., et al, Adverse Effects of Captopril in Hospital Outpatients with Hypertension, Post Grad. Med. Journ. 1990, 66: 106-109]. Others have shown that ACE inhibitors such as captopril do not show any effect on improving impotence. [Croog et al, Sexual Symptoms in Hypertensive Patients, Arch.Intern.Med 148: 788-794, (1988), Suzuki et al, Effect of First-line Antihypertensive Agents on Sexual Functions and Sex Harmones, J of Hypertension, 6:S649-S651 (1988)]
Several therapies have been formulated, recommended and employed for treatment of penile erectile dysfunction. Common therapies include treatment with androgens, injections into corpus cavernosum of smooth muscle relaxants such as papaverine, phentolamine, phenyl benzamine, prostaglandin E.sub.1 etc. Several mechanical devices such as those employing vacuum to produce erection and clips at the base of the penis to restrict and prevent venous return have also been suggested. While injections have been most successful in 70 to 95% cases, self injection is extremely cumbersome and more often than not, quite painful. Its side effects include penile fibrosis and priapism.
Towards avoiding the aforesaid drawbacks, U.S. Pat. No. 5,658,936 suggests a therapy, which could be administered systemically. The method disclosed in this patent involves treating patients having erectile dysfunction with renin-angiotensin system inhibitor particularly selected from the group consisting of angiotensin II antagonist, an ACE inhibitor or a renin inhibitor.
In an alternative approach, WO 94/28902 of Pfizer Limited teaches use of pyrazolopyrimidones for treatment of impotence. This patent also aims to overcome disadvantages of treatment by direct injection into the penis. This patent recognizes that while several drugs have been shown to induce penile erection, they are only effective after direct injection into the penis, e.g. intraurethrally or intracavernosally (i.c). These, however, are not approved for erectile dysfunction.
The above patent specification recognizes that potassium channel openers (KCO) and vasoactive intestinal polypeptide (VIP) have also shown to be active i.c., but costs and stability issues have impeded further research thereon.
As an alternative to i.c. mode of administration, application of glyceryl trinitrate (GTN) patches on the penis have been found to be effective. However, it is seen that these patches not only produce undesirable side effects in the user but also in the partner.
Various penile prostheses have also been suggested but since many of the potential users already have problems such as diabetes, there is a risk of infection and ischaemia.
Accordingly, WO 94/28902 teaches the new use of a known drug pyrazolopyrimidones for treatment of impotence. According to this publication, pyrazolopyrimidones compounds have been unexpectedly found useful in the treatment of erectile dysfunction. The greatest advantage of these compounds is that these may be administered orally, thereby obviating all the drawbacks associated with i.c. administration. Test results conducted on dogs and rats with dosages up to 3 mg/Kg, both intravenously (i. v.) and orally (p. o.) have apparently not shown any adverse acute toxicity and in mouse, even after doses of up to 100 mg/Kg, i. v., no deaths occurred.
Recent studies have however, shown that pyrazolopyrimidones compounds, particularly sildenafil citrate, are liable to be abused not only by males with erectile dysfunction, but also by those without any apparent dysfunction to improve erectile function. Some deaths by myocardial infarction due to over dose of these compounds have been reported. Worse still further deaths were reported which were not attributable to overdose. In fact, in the late March through mid-November 1998, during which more than six million out patients prescriptions, representing more than fifty million tablets were dispensed, the US FDA received reports of 130 US patients who died after having been prescribed this drug. Excluded from this were reports of 55 foreign patients, 35 with unverifiable information (from hearsay, rumor, the media, or unidentifiable reporters), and 22 with unconfirmed sildenafil use. Assuming even 1% truth in the excluded information, the number of deaths are quite large to cause concern.
Hence, there is a strong need for an alternative therapy for a substance having the advantages of the aforesaid compounds without its associated risk.
Over the last few decades, number of theories have been postulated to describe the physiology of erection to understand the role of various factors that may affect the normal functioning. The most important breakthrough has been the identification of nitric oxide (NO) as the major neurotransmitter involved in erection.